Amino Acids

, Volume 12, Issue 2, pp 179–184 | Cite as

Phenytoin protected mouse cortical cell cultures against neurotoxicity induced by kainate but not by NMDA

  • H. Furue
  • N. Fudamato
  • Y. Ohtubo
  • K. Yoshii
Full Papers


Phenytoin (PHT) protected cultured mouse cortex neurons against kainate-induced excitotoxicity, but failed to protect against the N-methyl-D-aspartate (NMDA)-induced excitotoxicity. The voltage-clamp experiments showed that PHT significantly blocked kainate-induced currents but did not block NMDA-induced currents in the cultured neurons. These results indicate that PHT protects the cultures by blocking non-NMDA receptors and suggest that PHT has clinical efficacy against neuronal cell death through the excessive stimulation of non-NMDA receptors.


Amino acids Excitotoxicity Voltage clamp Diphenylhydantoin DPH PHT LDH 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Benveniste H, Drejer J, Schousboe A, Diemer NH (1984) Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis. J Neurochem 43: 1369–1374PubMedGoogle Scholar
  2. Brewer GJ, Cotman CW (1989) Survival and growth of hippocampal neurons in defined medium at low density: advantages of a sandwich culture technique or low oxygen. Brain Res 494: 65–74PubMedGoogle Scholar
  3. Choi DW, Koh J, Peters S (1988) Pharmacology of glutamate neurotoxicity in cortical cell culture: attenuation by NMDA antagonists. J Neurosci 8: 185–196PubMedGoogle Scholar
  4. Cullen JP, Aldrete JA, Jankovsky L, Romoo-Salas F (1979) Protective action of phenytoin in cerebral ischemia. Anesth Analg 58: 165–169PubMedGoogle Scholar
  5. Fukuda A, Tabuse H, Ihara N, Tanabe J, Ikeda H, Kohama A (1983) Effects of phenytoin on regional cerebral blood flow, electroencephalogram, and electrolyte contents in cerebral blood and cerebral cortex following total cerebral ischemia in dogs. Circulatory Shock 10: 341–350PubMedGoogle Scholar
  6. Gill R, Foster AC, Woodruff GN (1987) Systemic administration of MK-801 protects against ischemia-induced hippocampal neurodegeneration in the gerbil. J Neurosci 7: 3343–3349PubMedGoogle Scholar
  7. Hao JX, Xu XJ, Aldskogius H, Seiger A, Wiesenfeldhallin Z (1991) The excitatory amino acid receptor antagonist MK-801 prevents the hypersensitivity induced by spinal cord ischemia in the rat. Exp Neurol 113: 182–191PubMedGoogle Scholar
  8. Kawano H, Sashihara S, Ohno K, Mita T, Kawamura M, Yoshii K (1994) Phenytoin, an antiepileptic drug, competitively blocked non-NMDA receptors produced by Xenopus oocytes. Neurosci Lett 166: 183–186PubMedGoogle Scholar
  9. Kirino T, Tamura A, Sano K (1990) Chronic maintenance of presynaptic terminals in gliotic hippocampus following ischemia. Brain Res 510: 17–25PubMedGoogle Scholar
  10. Koh JY, Choi DW (1987a) Effect of anticonvulsant drugs on glutamate neurotoxicity in cortical cell culture. Neurology 37: 319–322PubMedGoogle Scholar
  11. Koh JY, Choi DW (1987b) Quantitative determination of glutamate mediated cortical neuronal injury in cell culture by lactate dehydrogenase efflux assay. J Neurosci Methods 20: 83–90PubMedGoogle Scholar
  12. Matsuoka I, Syoto B, Kurihara K, Kubo S (1987) ADP-ribosylation of specific membrane proteins in pheochromocytoma and primary-cultured brain cells by botulinum neurotoxins type C and D. FEBS Lett 216: 295–299PubMedGoogle Scholar
  13. Matthews W, Connor JD (1977) Actions of iontophoretic phenytoin and medazepam on hippocampal neurons. J Pharmacol Exp Ther 201: 613–621PubMedGoogle Scholar
  14. McLean MJ, Macdonald RL (1983) Multiple actions of phenytoin on mouse spinal cord neurons in cell culture. J Pharmacol Exp Ther 227: 779–789PubMedGoogle Scholar
  15. Monaghan DT, Holets VR, Toy DW, Cotman CW (1983) Anatomical distributions of four pharmacologically distinct 3H-L-glutamate binding sites. Nature 306: 176–179PubMedGoogle Scholar
  16. Nicoll RA, Wojtowicz JM (1980) The effects of pentobarbital and related compounds on frog motoneurons. Brain Res 191: 225–237PubMedGoogle Scholar
  17. Rogawski MA, Porter RJ (1990) Antiepileptic drugs: Pharmacological mechanisms and clinical efficacy with consideration of promising developmental stage compounds. Pharmacol Rev 42: 223–286PubMedGoogle Scholar
  18. Sastry BSR, Phillis JW (1976) Antagonism of glutamate and acetylcholine excitation of rat cerebral conrtical neurones by diphenylhydantoin. Gen Pharmacol 7: 411–413PubMedGoogle Scholar
  19. Sheardown MJ, Nielsen EO, Hansen AJ, Jacobsen P, Honore T (1990) 2,3-Dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline: a neuroprotectant for cerebral ischemia. Science 247: 571–574PubMedGoogle Scholar
  20. Suzuki J, Abiko H, Mizoi K, Oba M, Yoshimoto T (1987) Protective effect of phenytoin and its enhanced action by combined administration with mannitol and vitamin E in cerebral ischaemia. Acta Neurochir 88: 56–64Google Scholar
  21. Twombly DA, Yoshii M, Narahashi T (1988) Mechanisms of calcium channel block by phenytoin. J Pharmacol Exp Ther 246: 189–195PubMedGoogle Scholar
  22. Wieloch T, Lindvall O, Blomqvist P, Gage FH (1985) Evidence for amelioration of ischaemic neuronal damage in the hippocampal formation by lesions of the perforant path. Neurol Res 7: 24–26PubMedGoogle Scholar
  23. Willow M, Gonoi T, Catterall WA (1985) Voltage clamp analysis of the inhibitory actions of diphenylhydantoin and carbamazepine on voltage-sensitive sodium channels in neuroblastoma cells. Mol Pharmacol 27: 549–558PubMedGoogle Scholar
  24. Zaczek R, Nelson MF, Coyle JT (1978) Effects of anaesthetics and anticonvulsants on the action of kainic acid in the rat hippocampus. Eur J Pharmacol 52: 323–327PubMedGoogle Scholar

Copyright information

© Springer-Verlag 1997

Authors and Affiliations

  • H. Furue
    • 1
  • N. Fudamato
    • 1
  • Y. Ohtubo
    • 1
  • K. Yoshii
    • 1
  1. 1.Department of Biochemical Engineering and ScienceKyushu Institute of TechnologyIizuka, FukuokaJapan

Personalised recommendations